Method of preparing N,N′-disubstituted-3,3′-dithiodipropionamide and method of preparing substituted 3-isothiazolone by using the same

ABSTRACT

A method of preparing N,N-disubstituted-3,3′-dithiodipropionamide of formula (2) is provided. In the method, 3-mercaptopropionamide of formula (4) reacts with an aqueous solution of amine to prepare N-substituted-3-mercaptopropionamide of formula (3) and                    
     N-substituted-3-mercaptopropionamide reacts with an aqueous solution of hydrogen peroxide. In addition, a method of preparing substituted 3-isothiazolone is provided. In the method, the produced N,N-disubstituted-3,3′-dithiodipropionamide reacts with a halogenating agent, wherein X and Z are same or different and each selected from the group consisting of hydrogen or a lower alkyl group; Y is selected from the group consisting of hydrogen, an alkyl group of 1 to 18 carbon atoms, a cycloalkyl group of up to 10 carbon atoms, an aralkyl group of up to 10 carbon atoms, an aryl group of up to 10 carbon atoms, a halogen-, lower alkyl- or lower alkoxy-substituted aryl group, a cyano alkyl group, a carboalkoxyalkyl group, a haloalkyl group, an alkoxyalkyl group, an aryloxyalkyl group of up to 12 carbon atoms, an aralkoxyalkyl group of up to 12 carbon atoms, a dialkylaminoalkyl group, an alkylacyl group of up to 8 carbon atoms, a lower alkylsulfonyl group, an arylsulfonyl group of up to 10 carbon atoms, a cyano group and a carbamoyl group.

This application is a 371 of PCT/KR99/00163, filed Apr. 3, 1999

BACKGROUND OF THE INVENTION

(a) Field of the Invention

The present invention relates to a method of preparing substituted3-isothiazolone and, more particularly, to a method of preparingN,N′-disubstituted-3,3′-dithiodipropionamide and a method of preparingsubstituted 3-isothiazolone by using the same as a intermediate.

(b) Description of the Related Art

The substituted 3-isothiazolone of the formula 1 which synthesized byCrow et al., is widely used for disinfectants, biocides or microbiocidesin paints, cosmetics or plastics.

wherein

Y is selected from the group consisting of hydrogen, an alkyl group of 1to 18 carbon atoms, a cycloalkyl group of up to 10 carbon atoms, anaralkyl group of up to 10 carbon atoms, an aryl group of up to 10 carbonatoms, a halogen-, lower alkyl-, or lower alkoxy-substituted aryl group,a cyanoalkyl group, a carboalkoxyalkyl group, a haloalkyl group, analkoxyalkyl group, an aryloxyalkyl group of up to 12 carbon atoms, anaralkoxyalkyl group of up to 12 carbon atoms, a dialkylaminoalkyl group,an alkylacyl group of up to 8 carbon atoms, a lower alkylsulfonyl group,an arylsulfonyl group of up to 10 carbon atoms, a cyano group and acarbamoyl group;

R₁ and R₂ are same or different and each selected from the groupconsisting of hydrogen, halogen and a lower alkyl group.

U.S. Pat. No. 3,849,430 discloses a method of preparing substituted3-isothiazolones. In the method,N,N′-disubstituted-3,3-dithiodipropionamide orN-substituted-3-mercaptopropionamide reacts with a halogenating agent,resulting in the cyclization of the amides. TheN,N′-disubstituted-3,3′-dithiodipropionamide is prepared by reacting3,3′-dithiodipropionic acid with amine in the form of gaseous atmosphereas the following reaction 1.

wherein Y is as defined above, X and Z are same or different and eachselected from the group consisting of hydrogen and a lower alky group, Ris selected from the group consisting of hydrogen, an alkyl group, aphenyl group, a cyano group, a sulfonyl group and a aminocarbonyl group.

The method can produces stableN,N′-disubstituted-3,3′-dithiodipropionamide with high yield. However,the produced N,N-disubstituted-3,3′-dithiodipropionamide has low purityand the reaction should be performed for a long time, i.e. 48 hours ormore than. Furthermore, as the method uses amine in the form of gaseousatmosphere, the safety and environmental problems may occur.

N-substituted-3-mercaptopropionamide is prepared by reacting3-mercaptopropionic acid. Prepared as described above, with alcohol toform 3-mercaptopropion ester and treating 3-mercaptopropion ester withamine in the form of gaseous atmosphere as the following reaction 2.

wherein X, Y, Z and R are as defined above.

The method can produce N-substituted-3-mercaptopropionamide with highyield and the reaction may be performed for a short time. i.e. less than24 hours. However, the produced N-substituted-3-mercaptopropionamide haslow purity. Furthermore, as the method uses amine in the form of gaseousatmosphere, the safety and environmental problems occur. Furthermore,water is generated during the method, that can substantially lower theyield of the subsequent halogenation reaction.

U.S. Pat. No. 4,868,310 discloses a method of preparingN-substituted-3-mercaptopropionamide. In the method, a mixture ofunsaturated nitrile and alcohol, and strong inorganic acid are cofed inan organic solvent to prepare acrylamide and acrylamide is treated witha thiolating agent. However, water is generated during the method andtherefore, the drying step is necessary.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method ofpreparing N,N′-disubstituted-3,3′-dithiodipropionamide having stableproperty with high yield within a short reaction time.

It is another object to provide the method of preparingN,N′-substituted-3,3′-dithiopriopionamide which can be easily controlledand has safety and environment advantages.

It is another object to provide a method of preparing substituted3-isothiazolone without generation of water.

It is another object to provide the method of preparing substituted3-isothiazolone with high yield.

These and other objects may be achieved by a method of preparingN,N-disubstituted-3,3′-dithiodipropionamide of formula 2 comprising thesteps of first-reacting 3-mercaptopropionamide of formula 4 with anaqueous solution of amine to prepareN-substituted-3-mercaptopropionamide of formula 3; and second-reactingN-substituted-3-mercaptopropionamide with an aqueous solution ofhydrogen peroxide.

wherein

X and Z are same or different and each selected from the groupconsisting of hydrogen or a lower alkyl group;

Y is selected from the group consisting of hydrogen, an alkyl group of 1to 18 carbon atoms, a cycloalkyl group of up to 10 carbon atoms, anaralkyl group of up to 10 carbon atoms, an aryl group of up to 10 carbonatoms, a halogen-, lower alkyl- or lower alkoxy-substituted aryl group,a cyano alkyd group, a carboalkoxyalkyl group, a haloalkyl group, analkoxyalkyl group, an aryloxyalkyl group of up to 12 carbon atoms, anaralkoxyalkyl group of up to 12 carbon atoms, a dialkylaminoalkyl group,an alkylacyl group of up to 8 carbon atoms, a lower alkylsulfonyl group,an arylsulfonyl group of up to 10 carbon atoms, a cyano group and acarbamoyl group.

In order to achieve these objects and others, the present inventionprovides a method of preparing substituted 3-isothiazolone comprisingthe steps of reacting 3-mercaptopropion ester of formula 4 with anaqueous solution of amine to prepareN-substituted-3-mercaptopropionamide of formula 3; reactingN-substituted-3-mercaptopropionamide with an aqueous solution ofhydrogen peroxide to prepareN,N-disubstituted-3,3′-dithiodipropionamide; and reactingN,N-disubstituted-3,3′-dithiodipropionamide with a halogenating agent.

The present invention further includes a method of preparing5-chloro-2-methyl-3-isothiazolone comprising the steps of reacting3-mercaptopropion ester with an aqueous solution of methyl amine toprepare N-methyl-3-mercaptopropionamide; reactingN-methyl-3-mercaptopropionamide with an aqueous solution of hydrogenperoixde to prepare N,N′-dimethyl-3,3′-dithiodipropionamide; andreacting N,N′-dimethyl-3,3′-dithiodipropionamide with a halogenatingagent selected from the group consisting of chlorine, sulfuryl chlorideand N-chlorosuccinimide.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of preparingN,N′-3,3′-disubstituted-3,3′-dithiodipropionamide.

In the method, 3-mercaptopropion ester of formula 4 reacts with anaqueous solution of amine to form N-substituted-3-mercaptopropionamide.N-substituted-3-mercaptopropionamide reacts with an aqueous solution ofhydrogen peroxide.

The present invention further provides a method of preparing substituted3-isothiazolone by using N,N′-disubstituted-3,3′-dithiodipropionamide asthe intermediate.

In the method, N,N′-disubstituted-3,3′-dithiodipropionamide reacts witha halogenating agent.

The methods of the present invention are illustrated in more details.

I. Preparation of N,N′-disubstituted-3,3′-dithiodipropionamide

[Reaction 3]

wherein X, Y, Z and R are as defined above.

An aqueous solution of amine is added to 3-mercaptopropion ester and themixture is shaken for more than 2 hours, preferably, 2 to 40 hours toreact. At this time, N-substituted-3-mercaptopropionamide is obtained.

1.0 to 1.5 equivalents of the aqueous solution of amine is preferablyadded per 1 equivalent of 3-mercaptopropion ester. The amount of amineaqueous solution is less than 1.0 equivalent, yield ofN-substituted-3-mercaptopropionamide is reduced. On the contrary, if theamount thereof exceeds 1.5 equivalents, the amount of the unreactedamines increases. The concentration of the aqueous solution of amine isless than 5%, the amounts of reactants increase and reaction efficiencydecreases.

In the step, as amine is used in the form of an aqueous solution ratherthan the gas, it is easily control reaction condition and the method hassafety and environment advantages.

Thereafter, the temperature is elevated, thereby to remove the producedalcohol and an organic solvent is added to the resulting product. Theorganic solvent may be toluene, 1-butanol, methylene chloride,chloroform, hexane, cyclohexane, benzene or the mixture thereof. If theorganic solvent is not used, it may be difficult to shake.

At least 10%, more preferably, 35 to 50% an aqueous solution of hydrogenperoxide is added to N-substituted-3-mercaptopropionamide and reactedfor more than 0.5 hours, preferably, 0.5 to 20 hours under up to roomtemperature. 0.4 to 5.5 equivalent of the aqueous solution of hydrogenperoxide is preferably added per 1 equivalent ofN-substituted-3-mercaptopropionamide.

The concentration of hydrogen peroxide aqueous solution is less than10%, the amount of the reactant increases and the reaction efficiencydecreases.

In the step, as the hydrogen peroxide is used in the form of the aqueoussolution, it is to also easily control the reaction condition.Furthermore, the method has safety and environments advantages.

II. Preparation of Substituted 3-isothiazolone

The produced N,N′-disubstituted-3,3′-dithiodipropionamide reacts with ahalogenating agent to form substituted 3-isothiazolone. At this time,drying of N,N′-disubstituted-3,3′-dithiodipropionamide is not necessary,because water is not generated in the preparation ofN,N′-disubstituted-3,3′-dithiodipropionamide.

The halogenating agent may be chlorine (Cl₂), bromine, sulfuryl chloride(SOCl₂), sulfuryl bromide, N-chlorosuccinimide or N-bromosuccinimide.

In the reaction 3, if X and Z are hydrogen, and Y is a methyl group, themethod of substituted 3-isothiazolone is as follows:

3-mercaptomethylpropione ester reacts with an aqueous solution of methylamine to prepare N-methyl-3-mercaptopropionamide.N-methyl-3-mercaptopriopionamide reacts with an aqueous solution ofhydrogen peroxide to prepare N,N′dimethyl-3,3′-dithiodipropionamide.Thereafter, N,N′-dimethyl-3,3′-dithiodipropionamide reacts with ahalogenating agent. The halogenating agent may be chlorine, sulfurylchloride and N-chlorosuccinimide. 5-chloro-2-methyl-3-isothiazolone isobtained.

The present invention will be now explained in more detail by referenceto examples which are not limited to the present invention.

I. Preparation of intermediate for producing substituted3-isothiazolone 1. Preparation of N,N′-methyl-3,3′-dithiodipropionamideEXAMPLE 1

100 g of an aqueous solution of methyl amine having a concentration of40% was added to 120 g of 3-mercaptomethylpropion ester under the roomtemperature and shaken for 17 hours to react.N-methyl-3-mercaptopropionamide was obtained. The temperature waselevated, thereby to remove the produced methanol and 200 g of toluenewas added to the resulting product. 25 g of an aqueous solution ofhydrogen peroxide having a concentration of 35% was slowly added to themixture under the room temperature and reacted for 0.5 hours. Thefiltrating step and drying step were performed.N,N′-dimethyl-3,3′-dithiodipropionamide was obtained.

EXAMPLE 2

N,N′-dimethyl-3,3′-dithiodipropionamide was prepared by the sameprocedure in Example 1 except that 200 g of methylene chloride was usedinstead of toluene.

EXAMPLE 3

N,N′-dimethyl-3,3′-dithiodipropionamide was prepared by the sameprocedure in Example 1 except that 200 g of cyclehexane was used insteadof toluene.

EXAMPLE 4

N,N′-dimethyl-3,3′-dithiodipropionamide was prepared by the sameprocedure in Example 1 except that 200 g of 1-butanol was used insteadof toluene.

Comparative Example 1

40 g of methyl amine in the form of gaseous atmosphere was injected into119 g of N,N′-dimethyl-3,3′-dithiodipropion ester under the roomtemperature for two hours. At this time, pressure was elevated to 4 atm.After shaking for 40 hours, temperature increased to 65° C., thereby toremove methanol and excess methyl amine.N,N′-dimethyl-3,3′-dithiodipropionamide was obtained.

2. Preparation of N-methyl-3-mercaptopropionamide Comparative Example 2

40 g of methyl amine in the from of gaseous atmosphere was injected into120 g of 3-mercaptomethypropion ester under the room temperature for 2hours. At this time, pressure was elevated to 4 atm. After shaking 17hours, temperature was elevated to 65° C., thereby to remove methanoland excess methyl amine. N-methyl-3-mercaptopropionamide was obtained.

The yield, purity, reaction time, reaction pressure and water content ofproducts of examples 1-4 and comparative examples 1-2 were determinedand the results are shown in Table 1.

TABLE 1 Reaction Reaction Yield Purity time pressure Water [%] [%][hour] [atm] content [%] Example 1 92 99 17 0 — Example 2 91 98 17 0 —Example 3 91 98 17 0 — Example 4 91 98 17 0 — Comparative 80 80 40 4 —example 1 Comparative 95 93 17 4 2.5 example 2

As shown in Table 1, examples 1-4 can produce desired products with highyield and purity within a short reaction time. Furthermore, as reactionpressures are low in examples 1-4, it is easy to control reactionconditions. Particularly, water is not generated in examples 1-4, thatcan substantially lower the yield of the subsequent halogenationreaction for producing substituted 3-isothiazolone.

In the comparative example 1, low reaction speed due to physicalproperty of N,N′-disubstituted-3,3′-dithiodipropion ester causedextension of the amide reaction time and decreases of yield.Furthermore, as gaseous atmosphere including amine causes increase ofpressure, it is require further equipment for controlling pressure andit is difficult to control the reaction condition.

The comparative example 2 has the problems caused by gaseous amine aswell as “—SH” group in molecular. When a compound including “—SH” groupwas contacted with air, the compound including “—SH” group oxides,thereby to form water. The formed water decreases yield of thehalogenation yield.

II. Preparation of 5-chloro-2-methyl-3-isothiazolone EXAMPLE 5

200 g of ethanol was added to 28.9 g ofN,N′-dimethyl-3,3′-dithiodipropionamide obtained in example 1 and 70 gof sulfuryl chloride (SO₂Cl₂) was added to the mixture.5-chloro-2-methyl-3-isothiazolone was obtained.

EXAMPLES 6-8

5-chloro-2-methyl-3-isothiazolone were prepared by the same procedure inExample 5 except that N,N′-dimethyl-3,3′-dithiodipropionamide obtainedin Examples 2-4 were used, respectively.

Comparative Example 3

5-chloro-2-methyl-3-isothiazolone was prepared by the same procedure inExample 5 except that N,N′-dimethyl-3,3′-dithiodipropionamide obtainedin comparative example was used.

Comparative Example 4

5-chloro-2-methyl-3-isothiazolone was prepared by the same proceudre inExample 5 except that N-methyl-3-mercaptopropionamide was used.

The yields of products obtained in examples 5-8 and comparative examples34 were determined and the results are shown in Table 2.

TABLE 2 Yield [%] Example 5 85 Example 6 85 Example 7 84 Example 8 85Comparative example 3 78 Comparative example 4 65

As shown in Table 2, examples 5-8 can produce5-chloro-2-methy-3-isothiazolone, substituted 3-isothiazolone, with highyield.

The method of the present invention can produce stableN,N′-disubstituted-3,3′-dithiodipropionamide with high yield and reducethe reaction time. Furthermore, it is easy to control the reactioncondition, the method has safety and environment advantages. As water isnot generated during the method, drying step ofN,N′-disubstituted-3,3′-dithiopropionamide is not necessary before thehalogen reaction and produce 3-isothiazolone with high yield.

While the present invention has been described in detail with referenceto the preferred embodiments, those skilled in the art will appreciatethat various modifications and substitutions can be made thereto withoutdeparting from the spirit and scope of the present invention as setforth in the appended claims.

What is claimed is:
 1. A method of preparingN,N-disubstituted-3,3′-dithiodipropionamide of formula 2 comprising thesteps of: first-reacting 3-mercaptopropionamide of formula 4 with anaqueous solution of amine to prepareN-substituted-3-mercaptopropionamide of formula 3; second-reactingN-substituted-3-mercaptopropionamide with an aqueous solution ofhydrogen peroxide;

 wherein X and Z are same or different and each selected from the groupconsisting of hydrogen or a lower alkyl group; Y is selected from thegroup consisting of hydrogen, an alkyl group of 1 to 18 carbon atoms, acycloalkyl group of up to 10 carbon atoms, an aralkyl group of up to 10carbon atoms, an aryl group of up to 10 carbon atoms, a halogen-, loweralkyl- or lower alkoxy-substituted aryl group, a cyano alkyl group, acarboalkoxyalkyl group, a haloalkyl group, an alkoxyalkyl group, anaryloxyalkyl group of up to 12 carbon atoms, an aralkoxyalkyl group ofup to 12 carbon atoms, a dialkylaminoalkyl group, an alkylacyl group ofup to 8 carbon atoms, a lower alkylsulfonyl group, an arylsulfonyl groupof up to 10 carbon atoms, a cyano group and a carbamoyl group.
 2. Themethod of claim 1, wherein the first-reacting step is performed byadding 1.0 to 1.5 equivalents of aqueous solution of amine to3-mercaptopropione ester and reacting the mixture for more than 2 hoursunder the room temperature.
 3. The method of claim 1, wherein thesecond-reacting step is performed by adding 0.4 to 5.5 equivalents ofaqueous solution of hydrogen peroxide having a concentration of at least10% in an oragnic solvent and reacting the mixture for more than 0.5hours under up to room temperature.
 4. The method of claim 3, whereinthe organic solvent is selected from the group consisting of toluene,1-butanol, methylene chloride, chloroform, hexane, cyclohexane, benzeneand the mixture thereof.
 5. The method of claim 1, wherein X and Z arehydrogen and Y is methyl group.